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Impact of Genetic Variants on the Toxicity of Antibody-Drug Conjugates in Locally Advanced or Metastatic Breast Cancer: The Role of the UGT1A1 Gene as a Predictive Biomarker of Therapeutic Response

NCT07582887 · Status: RECRUITING · Type: OBSERVATIONAL · Enrollment: 70

Last updated 2026-05-13

No results posted yet for this study

Summary

The metabolism of anticancer drugs is influenced by genetic variants that affect their bioavailability and toxicity. In the case of antibody-drug conjugates (ADCs), such as sacituzumab-govitecan (SG), trastuzumab-deruxtecan (T-DXd), and datopotamab-deruxtecan (Dato-DXd), the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a central role in the glucuronidation and elimination of their cytotoxic components. In particular, the metabolism of SN-38, the active metabolite of irinotecan and SG, is highly influenced by variants in UGT1A1, leading to drug accumulation and the development of severe toxicities. Patients with variants such as UGT1A1\*28 (rs3064744) and UGT1A1\*6 (rs4148323) exhibit reduced enzyme activity, increasing the risk of neutropenia and severe diarrhea.

The relevance of UGT1A1 is not limited to sacituzumab-govitecan; its role in the elimination of camptothecin derivatives suggests it could also impact the toxicity of trastuzumab-deruxtecan and datopotamab-deruxtecan, which contain deruxtecan, a cytotoxic agent 10 times more potent than irinotecan. Despite strong evidence linking the UGT1A1 genotype to irinotecan toxicity, there are currently no established pharmacogenetic recommendations for antidiuretic peptides (ADCs) in metastatic breast cancer.

Conditions

Interventions

DRUG

Sacituzumab Govitecan

Administered according to standard clinical practice and product label.

DRUG

Trastuzumab deruxtecan

Administered according to standard clinical practice and product label.

DRUG

Datopotamab Deruxtecan

Administered according to standard clinical practice and product label.

Sponsors & Collaborators

  • Fundación Pública Andaluza para la Investigación Biomédica Andalucía Oriental

    lead OTHER

Eligibility

Min Age
18 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2025-07-15
Primary Completion
2026-12-31
Completion
2027-03-31

Countries

  • Spain

Study Locations

More Related Trials

Entities

Drugs
Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT07582887 on ClinicalTrials.gov